کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1361430 981463 2008 18 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Discovery of sulfonylalkylamides: A new class of orally active factor Xa inhibitors
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Discovery of sulfonylalkylamides: A new class of orally active factor Xa inhibitors
چکیده انگلیسی

Factor Xa (FXa) is a trypsin-like serine protease involved in the coagulation cascade and has received great interest as a potential target for the development of new antithrombotic agents. Most of amidine-type FXa inhibitors reported have been found to show extremely poor oral bioavailability. Compound 1 is one of the first reported non-amidine type FXa inhibitors. To discover novel and orally active FXa inhibitors, we investigated flexible linear linkers between the 6-chloronaphthalene ring and the 1-(pyridin-4-yl)piperidine moiety of 1 and found the orally active sulfonylalkylamide 2f with an FXa IC50 of 0.05 μM, comparable with that of 1. Further modification to reduce the CYP3A4 inhibitory activity of 2f resulted in the potent, selective, and orally active 2-methylpyridine analogue 2s (FXa IC50 of 0.061 μM), for which the liability of CYP3A4 inhibition was significantly weakened compared to 2f. Compound 2s also showed long lasting anticoagulant activity in cynomolgus monkeys.

Synthesis, structure–activity relationships, ex vivo anticoagulant activities, selectivity, and pharmacokinetics of sulfonylalkylamides 2 as novel non-amidine FXa inhibitors are reported.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 16, Issue 5, 1 March 2008, Pages 2243–2260
نویسندگان
, , , , , , , , ,